ABSTRACT/SUMMARY Alcohol-use disorder (AUD) is an unrelenting public-health concern. AUD is characterized by perturbations of central monoamine (i.e., dopamine [DA], serotonin [5HT], and norepinephrine [NE]) systems making them a logical target for medications development. Individual monoamine-uptake inhibitors were moderately effective in a majority of the trials in which they were tested for managing AUD. Continuing to target monoamine-uptake inhibition for AUD is warranted, but novel strategies are needed to identify a highly efficacious pharmacotherapy. We propose to demonstrate the initial efficacy of an innovative pharmacological strategy for managing AUD: Triple Monoamine-Uptake Inhibition. Triple monoamine-uptake inhibitors are under development, but are not yet available commercially for human use. Combining available medications, however, makes it possible to achieve triple monoamine-uptake inhibition. Duloxetine (DUL), an antidepressant, has high affinity for the 5HT (ki = 0.8 nM) and NE (ki = 7.5 nM) transporters, but lower affinity for the DA transporter (ki = 240 nM). Methylphenidate (MTH) has high affinity for the DA transporter (ki = 34 nM), but lower affinity for the 5HT (ki = >10,000 nM) and NE (ki = 339 nM) transporters. We will combine DUL and MTH to functionally produce a triple monoamine-uptake inhibitor. A mixed-model study will be conducted in which separate cohorts of non-treatment-seeking AUD participants will be randomized to different maintenance doses of delayed-release DUL (i.e., DUL dose is a between-subject factor). Participants (N=16) in each DUL cohort will be maintained concurrently on increasing doses of long-acting MTH (i.e., MTH dose is a within-subject factor). Alcohol (ALC) self-administration will be determined after participants in each DUL cohort are maintained for 6 days on each MTH dose. A reverse-engineered ALC self-administration (ALC SA) procedure with good predictive validity for clinical efficacy will be used to demonstrate the initial efficacy of DUL-MTH combinations. ALC craving will also be assessed. We hypothesize DUL-MTH combinations will produce an additive or supra-additive reduction in ALC SA relative to the constituent drugs alone. Innovations include: 1) testing a novel pharmacological strategy, triple monoamine-uptake inhibition, for AUD; 2) testing a combination of marketed drugs as opposed to waiting for compounds under development to be available for testing in humans, thereby impacting clinical research and practice more quickly; 3) the use of once daily dosing formulations of the constituent compounds which will improve compliance when advanced to clinical trials or practice; 4) the use of a sophisticated ALC SA procedure; 5) testing multiple doses of DUL and MTH alone and in combination to identify the most effective, safe and tolerable dose combination which will enhance the probability of success when advanced to a clinical trial or practice; and 6) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of DUL-MTH combinations for AUD.